Persistent STAT5 activation reprograms the epigenetic landscape in CD4 + T cells to drive polyfunctionality and antitumor immunity
| Autor: | Richard A. McIndoe, Eun Jeong Park, David H. Munn, Nada S. Aboelella, Gary A. Piazza, Zhuoqi Liu, Hongyan Xu, Jiaqi Li, Lirong Pei, Kateryna Fesenkova, Bruce R. Blazar, Zhi-Chun Ding, Gang Zhou, Huidong Shi |
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| Rok vydání: | 2020 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male Adoptive cell transfer Lymphoma T cell medicine.medical_treatment Primary Cell Culture Immunology Mice Transgenic Immunotherapy Adoptive Article Epigenesis Genetic Mice Single-cell analysis Transduction Genetic Cell Line Tumor STAT5 Transcription Factor medicine Animals Humans RNA-Seq Epigenetics Receptors Chimeric Antigen Chemistry General Medicine Immunotherapy Chimeric antigen receptor Cell biology Gene Expression Regulation Neoplastic Disease Models Animal medicine.anatomical_structure Cell culture Female Single-Cell Analysis CD8 |
| Zdroj: | Sci Immunol |
| ISSN: | 2470-9468 |
| Popis: | The presence of polyfunctional CD4(+) T cells is often associated with favorable antitumor immunity. We report here that persistent activation of signal transducer and activator of transcription 5 (STAT5) in tumor-specific CD4(+) T cells drives the development of polyfunctional T cells. We showed that ectopic expression of a constitutively active form of murine STAT5A (CASTAT5) enabled tumor-specific CD4(+) T cells to undergo robust expansion, infiltrate tumors vigorously and elicit antitumor CD8(+) T cell responses in a CD4(+) T-cell adoptive transfer model system. Integrated epigenomic and transcriptomic analysis revealed that CASTAT5 induced genome-wide chromatin remodeling in CD4(+) T cells and established a distinct epigenetic and transcriptional landscape. Single-cell RNA sequencing analysis further identified a subset of CASTAT5-transduced CD4(+) T cells with a molecular signature indicative of progenitor polyfunctional T cells. The therapeutic significance of CASTAT5 came from our finding that adoptive transfer of T cells engineered to co-express CD19-targeting chimeric antigen receptor (CAR) and CASTAT5 gave rise to polyfunctional CD4(+) CAR T cells in a mouse B-cell lymphoma model. Notably, the optimal therapeutic outcome was obtained when both CD4(+) and CD8(+) CAR T cells were transduced with CASTAT5, indicating that CASTAT5 facilitates productive CD4 help to CD8(+) T cells. Furthermore, we provide evidence that CASTAT5 is functional in primary human CD4(+) T cells, underscoring its potential clinical relevance. Our results implicate STAT5 as a valid candidate for T cell engineering to generate polyfunctional, exhaustion-resistant, and tumor-tropic antitumor CD4(+) T cells to potentiate adoptive T-cell therapy for cancer. |
| Databáze: | OpenAIRE |
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